This revised competing renewal Program Project application request funds to continue studies on the molecular mechanisms of HIV-1 associated encephalopathy. Our research during the first funding period was marked by establishment of synergistic collaborations among PPG investigators, program-wide access to patient and fetal tissues and primary neural cells permitting studies on neuropathogenesis in natural systems, and complementation among the different disciplines represented by different disciplines represented by individual projects. 57 publication resulted from the first funding period. Significant progress has been made in most of the originally proposed studies with these major findings: we elucidated neurotoxic effects and neuron apoptosis mediated by factors released from HIV-1 infected macrophages, developed a novel animal model for neuropathogenesis, demonstrated restricted HIV-1 infection in astrocytes in vivo and in vitro, isolated and partially cloned primary astrocytotropic HIV-1 from the CNS, and demonstrated deleterious effects of TNFa. HIV-1 infection, and gp120 exposure on glutamate uptake by primary astrocytes. Our research validated the role of HIV-1 infected macrophages in AIDS neuropathogenesis and developed a new concept of direct pathogenic effects of HIV-1 through infection of astrocytes and disruption of their neuroprotective function. These two complementary models of neuropathogenesis will be pursued in parallel in vitro and in vivo studies during next funding period.